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Indication: For the treatment of adults with active ankylosing spondylitis who have had an inadequate response to a biologic disease-modifying antirheumatic drug or when use of those therapies is inadvisable. Upadacitinib may be used as monotherapy or in combination with nonsteroidal anti-inflammatory drugs
CADTH recommends that Rinvoq be reimbursed for the treatment of adults with active ankylosing spondylitis (AS) who have had an inadequate response to a biologic disease-modifying antirheumatic drug (bDMARD) or when use of those therapies is inadvisable only if certain conditions are met.
Eligibility for Rinvoq should be based on the criteria used by each of the public drug plans for reimbursement of bDMARDs for the treatment of adult with active AS who have had an inadequate response to a bDMARD, are intolerant, or who have contraindications to bDMARDs.
Rinvoq should only be reimbursed if it is prescribed by a rheumatologist. For patients with other manifestations, an ophthalmologist, gastroenterologist, or dermatologist may be consulted. Rinvoq should not be reimbursed when used in combination with bDMARDs or other Janus kinase (JAK) inhibitor treatments for active AS. The cost of Rinvoq should not exceed the drug program cost of treatment with the least expensive bDMARD reimbursed for the treatment of AS.
AS (also referred to as radiographic axial spondyloarthritis) is a chronic inflammatory disease primarily involving the spine and the sacroiliac joints. Patients with AS experience back pain and spinal stiffness that negatively affect their quality of life. In 2019, AS was estimated to affect 300,000 people in Canada. The goals of treatment for patients with AS are to maximize long-term health-related quality of life, control symptoms and inflammation, maintain spinal flexibility and normal posture, reduce functional limitations, maintain work ability, decrease disease complications, and prevent progressive structural damage.
Not all patients with AS respond to currently available treatments. Patients on AS medications experience various adverse effects with current therapies; report that medications become less effective more frequently, which requires a switch to another medication; and experience the persistence of constant spinal pain and active extra-articular manifestations. Finally, the lack of orally administrated treatment options affects compliance and adherence to the treatment plan.
Treatment with Rinvoq is expected to cost approximately $17,965 per patient per year.
The CADTH Canadian Drug Expert Committee (CDEC) recommends that upadacitinib be reimbursed for the treatment of adults with active ankylosing spondylitis (AS) who have had an inadequate response to a biologic disease-modifying antirheumatic drug (bDMARD) or when use of those therapies is inadvisable only if the conditions listed in Table 1 are met.
Two double-blind, randomized controlled trials (Study 944 [N = 420] for patients with AS who inadequately responded or were intolerant to 1 or 2 bDMARDs and Study 098 [N = 187] for patients with AS who inadequately responded or were intolerant to ≥ 2 nonsteroidal anti-inflammatory drugs [NSAIDs] but were bDMARD-naive) demonstrated that, compared with placebo, treatment with upadacitinib 15 mg orally once daily at 14 weeks was associated with statistically significant and clinically meaningful improvements in clinical response as measured by Assessment in SpondyloArthritis international Society 40% (ASAS 40). The difference between upadacitinib 15 mg and placebo groups in ASAS 40 response was 26.4% (95% confidence interval [CI], 17.9% to 34.9%) in Study 944 and 26.1% (95% CI, 12.6% to 39.5%) in Study 098. Treatment with upadacitinib 15 mg orally once daily at 14 weeks was also associated with statistically significant improvements for key secondary outcomes in both Study 944 and Study 098, including AS symptom reduction (e.g., total back pain), function and disability improvement (i.e., Bath Ankylosing Spondylitis Functional Index [BASFI] score), and AS disease activity reduction (e.g., Bath Ankylosing Spondylitis Disease Activity Index [BASDAI 50] score). In patients treated with upadacitinib, health-related quality of life (HRQoL) improved in Study 944, while MRI-detected axial inflammation improved in Study 098. Furthermore, the overall efficacy achieved at week 14 appeared to be maintained at 52 weeks ██████████████████ and week 104 (for Study 098). Adverse events (AEs) were aligned with the known safety profile of upadacitinib. No new safety signals were identified at weeks 14 and up to week 104. The evidence from 3 indirect treatment comparisons (ITCs) suggested that ██████████████████████████ ████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████
Based on the evidence reviewed, CDEC concluded that upadacitinib met some of the needs identified as important by patients, such as reducing AS symptoms, reducing disease activity, and improving HRQoL.
At the sponsor-submitted price for upadacitinib and publicly listed prices of all relevant comparators, upadacitinib was more costly than several relevant comparators used in the treatment of adults with active AS who have had an inadequate response to a bDMARD or when use of those therapies is inadvisable. Given the lack of direct comparative evidence and the findings from the ITCs suggesting upadacitinib was no more effective than available bDMARDs, there is insufficient evidence to justify a cost premium over the least expensive bDMARD reimbursed for the treatment of active AS.
Reimbursement Conditions and Reasons.
AS (also referred as radiographic axial spondyloarthritis) is a chronic inflammatory disease primarily involving the spine and the sacroiliac joints. Patients with AS exhibit radiographic abnormalities consistent with sacroiliitis. Patients experience back pain and progressive spinal stiffness and may also suffer from extra-articular manifestations, such as uveitis, skin psoriasis, and inflammatory bowel disease. The AS symptoms and the rate of progression fluctuate with time and can vary substantially between patients. AS negatively impacts patients’ HRQoL. A diagnosis of AS can be made based on the clinical features, biological testing, and imaging examinations of the disease. The modified New York classification criteria for AS have often been used as a diagnostic instrument. A Canadian population-based study published by Haroon et al. showed that the prevalence of AS nearly tripled in Ontario from 1995 to 2010, with the 2010 estimate being 0.2%. In the same study, the annual incidence of AS remained relatively stable with a rate of 15 per 100,000 population. In 2019, AS was estimated to affect 300,000 people in Canada. The goals of treatment for patients with AS are to maximize long-term HRQoL, to control symptoms and inflammation, maintain spinal flexibility and normal posture, reduce functional limitations, maintain work ability, decrease disease complications, and prevent progressive structural damage. Several drug classes are used in the pharmacologic therapy of AS.NSAIDs, including nonselective and selective cyclooxygenase-2 inhibitors, are the first choice of treatment for adult patients with active AS. Should NSAIDs fail or if there are contraindications, the next line of treatment is bDMARDs, including TNF inhibitors and IL-17 inhibitors or JAK inhibitors. Current practice is to start a TNF inhibitor or IL-17 inhibitor. TNF inhibitors marketed in Canada for treatment of AS include adalimumab, certolizumab, etanercept, golimumab, and infliximab. IL-17 inhibitors marketed in Canada for the treatment of AS include ixekizumab and secukinumab.
Upadacitinib has been approved by Health Canada for the treatment of adults with active AS who have had an inadequate response to a bDMARD or when use of those therapies is inadvisable. Upadacitinib may be used as monotherapy or in combination with NSAIDs. Upadacitinib is an oral, selective JAK inhibitor. JAK inhibitors are also classified as targeted synthetic DMARDs (tsDMARDs). It is available as 15 mg and 30 mg extended-release oral tablets. The recommended dose regimen in patients with AS is 15 mg, orally, once daily.
To make its recommendation, the committee considered the following information:
The information in this section is a summary of input provided by the patient groups who responded to CADTH’s call for patient input and from the clinical expert consulted by CADTH for the purpose of this review.
Two responses to CADTH’s call for patient input for this review were received from ACE and through a joint submission from CAPA, Arthritis Society Canada, CSA, and Creaky Joints Canada. All these groups serve individuals living with arthritis, including AS, and their caregivers, health care providers, and community members.
Patient perspectives from the joint input were obtained from a survey shared via email, social media, and the 4 organizations’ websites from October 12, 2022, to October 30, 2022. Patient perspectives from the ACE input were obtained from an ACE Survey Monkey platform.
Of the total of 264 joint survey participants living with AS, 9 patients had direct experience with upadacitinib. Almost 90% of the survey respondents indicated they live with back pain while 72% have back pain, 86% have joint stiffness, and 51% experience sore heels and feet. Patient respondents also had other symptoms of AS, such as anxiety and depression (52%), bowel inflammation (49%), psoriasis (35%), migraine (32%), uveitis (31%), osteoporosis (23%), and heart problems (11%). Most survey participants rated their disease severity as 59 out of 100. In addition, patients indicated they had trouble managing symptoms, including fatigue, difficulty concentrating, stress, mobility issues, and loss of appetite. Similarly, patient respondents from the ACE patient input indicated that they suffer from fatigue, mobility issues, weight gain, and constant pain, indicating that the disease affects their quality of life, their daily activities, and their mood. In addition, caregivers of patient respondents from the ACE input stated that the disease also impacted their quality of life because they must pay attention to their time management; when patients are in pain, caregivers have to help with house chores and many other aspects of life at home.
The joint patient input stated that during an AS flare (a period of worsening symptoms), patients may have difficulties performing day-to-day activities. Patient respondents with AS reported that the disease severely affects all aspects of their lives, from their physical and mental health to their family life, self-esteem, work, intimacy, and participation in social and leisure activities.
According to the joint patient input, many treatments are available to manage AS, including NSAIDs, corticosteroids, conventional synthetic DMARDs, and bDMARDs. The joint patient input stated that the effectiveness and tolerance of these treatments vary significantly between patients, with more than 40% of 264 patient respondents indicating that they had an inadequate response to currently available treatments. The joint patient input indicated that some patients had to change their medication after a short period of time; others did not respond adequately to the currently available treatments. In addition, the joint patient input indicated that side effects of current AS medications were another major concern for people living with AS. Fatigue, nausea and vomiting, increased risk of infections, liver toxicity, and weight gain affect patients’ adherence to medication and their daily activities.
According to the patient respondents from the ACE patient input, currently available treatments are good in managing their disease symptoms. However, concerns were raised regarding the cost of the medications, side effects, and changing medications due to decreased effectiveness within a short period of time.
The joint patient input highlighted that other treatment options, such as medical cannabis and/or nonpharmacological approaches to managing AS symptoms, are challenging to access because they are not reimbursed, not offered, or because these options require lengthy waits. According to the joint patient input, many factors need to be considered by health care providers to determine the most effective treatment, such as side effects, mode of administration, time required for treatment, travel, patient preferences, and cost.
Nine respondents from the joint input reported having experience with upadacitinib. Positive aspects of treatment with upadacitinib reported by patient respondents included the simple route of administration, improved disease symptoms, mobility, and better quality of life with more energy. Few patient respondents experienced more frequent infections and headaches from treatment with upadacitinib.
Patient respondents from the joint patient input stated that managing AS can be improved by having access to affordable treatments that have a simple administration route (e.g., pills), fewer adverse effects and infection rates, and are also able to reduce disease-related symptoms, improve their quality of life, and enable them to pursue their daily activities. The ACE patient input highlighted that patient respondents value additional treatment options with fewer AEs and improved pain control and remission rates.
The clinical experts consulted by CADTH for this review indicated that not all patients respond to available treatments. The ASAS40 is a common primary end point in clinical trials, which corresponds to a 40% improvement in 3 of 4 domains (patient global, total back pain, BASFI, and morning stiffness), with an absolute improvement of at least 2 domains and no worsening of the remaining domain. Approximately 40% of patients are able to achieve this response in clinical trials. More stringent measures of response, such as ASAS partial remission or Ankylosing Spondylitis Disease Activity Score (ASDAS) inactive disease, are much lower. Approximately 10% of patients with AS also have inflammatory bowel disease (IBD). Although TNF inhibitors can be effective to treat both, many patients with severe IBD do not respond to TNF inhibitors even at a very high dose (infliximab10 mg/kg every 4 weeks), initially respond but lose efficacy, or have to stop due to side effects (i.e., drug-induced psoriasis, lupus, or multiple sclerosis). IL-17 inhibitors would be contraindicated in these patients which does not leave many further options available to patients. For approximately half of patients, the efficacy of their first biologic is lost within 3 to 5 years. When patients inadequately respond to treatment with a biologic, clinicians often consider switching to a different mechanism of action if there is inadequate efficacy. If they have a secondary loss of effect, clinicians can consider switching within a class. Additionally, some patients may have a contraindication to available therapies. With TNF inhibitors, clinicians are cautious in patients with a personal or family history of multiple sclerosis, lupus, or drug-induced psoriasis. With IL-17 inhibitors, clinicians would try to avoid these agents in patients with a history of IBD. Finally, there are no oral bDMARD options available, and many patients are younger, or have an aversion to needles.
The clinical experts consulted by CADTH for this review indicated that treatment data from the upadacitinib trials in axial spondyloarthritis show treatment response rates that seem comparable to biologic agents, such as TNF and IL-17 inhibitors. JAK inhibitors do not seem to work through a TNF or IL-17 pathway so having an alternative mechanism of action would be ideal for these patients. Upadacitinib has been shown to reduce objective markers of inflammation such as C-reactive protein (CRP) and bone marrow edema in the sacroiliac joints and spine on MRI. Bone marrow edema has been shown to be a strong predictor of future syndesmophyte formation. If a patient requires an escalation in therapy, clinicians will decide whether a TNF, IL17, or JAK inhibitor would be the most appropriate and initiate therapy. Currently, the approved Health Canada label is to use these agents if a previous biologic has failed or if biologics are unsuitable; most rheumatologists were disappointed with that decision and were hoping to use this drug as a first-line DMARD drug in the appropriate patient. Upadacitinib was recently shown to be effective for non-radiographic axial spondyloarthritis with a sufficient sample size; therefore, the expectation is that the sponsor will want Health Canada approval for use as a first-line drug for this indication. The drug under review would provide further options to treat patients either due to contraindications to TNF and IL-17 inhibitors, previous failures to these drugs, convenience to patients by giving them an oral option, and efficacy in patients with both IBD and axial spondyloarthritis. Patients should try 2 NSAIDs for 2 to 4 weeks first unless there is a contraindication. If they still have high disease activity, DMARDs are expected to be a first-line option available to patients along with a TNF and IL-17 inhibitor. With the current Health Canada indication as a second-line drug, upadacitinib could be used if patients have previously failed a biologic or have a contraindication. Because upadacitinib has been approved to treat rheumatoid arthritis, most rheumatologists are comfortable with using it as a first-line biologic drug from a safety perspective.
The clinical experts consulted by CADTH for this review indicated that any patient with active AS would likely benefit from treatment with upadacitinib. Patients who also have active IBD prefer an oral option; and patients who had treatment with a TNF/ or IL-17 inhibitor that has failed or who have a contraindication to a TNF or IL-17 inhibitor may also benefit. Patients with high disease activity are in most need of an intervention. Elevated CRP levels and bone marrow edema on MRI may predict a higher response, but many patients with neither of these will also respond very well. The diagnosis of AS involves characteristic clinical findings in conjunction with identifying sacroiliitis in a pelvic X-ray. There can be considerable inter-reader reliability issues, especially with early disease. Many rheumatologists typically confirm a diagnosis with a sacroiliac joint MRI before proceeding with a bDMARD. The probability of under- or over-diagnosis is largely related to the experience of the clinician. Most cases are quite straightforward; convincing imaging, clinical features, and possibly a positive HLA-B27 can help the rheumatologist make the correct diagnosis. Additionally, the experience of the radiologist reading the X-ray, CT, or MRI is also important. Predictors of treatment response would be early onset of symptoms, male sex, CRP elevation, and the degree of bone marrow edema seen on MRI.
The clinical experts consulted by CADTH for this review indicated that clinicians typically follow up with a patient after 3 months of therapy. If there is absolutely no response, clinicians would consider switching to a different drug. If there is partial response, clinicians may wait up to 6 months to determine benefit. In daily practice, treatment response is measured by improvement in BASDAI or ASDAS. Typically, for BASDAI score, a decrease by at least 2 units or a 50% reduction from baseline score is a reasonable response. Clinicians would see patients every 3 to 6 months to ensure stability of their disease. In clinical trials, clinicians want to see an ASAS response of approximately 40% and statistically significant improvement in other measures, such as ASDAS change from baseline, CRP levels, MRI, ASAS Health Index, Ankylosing Spondylitis Quality of Life (ASQoL), and BASFI. The clinical experts consulted by CADTH for this review indicated that clinicians would discontinue the medication if patients developed side effects such as infections. If a patient’s symptoms were to recur, clinicians may consider switching to another medication if they were convinced that this was due to active disease The clinical experts consulted by CADTH for this review indicated a rheumatologist would be needed to confirm a diagnosis, treat, and monitor patients with AS. If there are other manifestations involved, they may also be followed by an ophthalmologist, gastroenterologist, and/or dermatologist.
CRA provided the clinical group input. Two clinicians, who are members of the Spondyloarthritis Research Consortium of Canada (SPARCC) executive committee and were involved in the 2014 CRA/SPARCC treatment recommendations, contributed to these submissions.
The clinician group indicated that there is an unmet need for the treatment of patients with AS for the following reasons: not all patients respond to currently available treatments; medications become less effective more frequently, which requires a switch to another medication; various adverse effects of the current therapies; persistence of constant spinal pain; and active extraarticular manifestations are common. There is also a lack of orally administered options, which affects compliance and adherence to the treatment plan.
The views of the clinician group were overall consistent with those of the clinical experts consulted by CADTH. The clinician group indicated that the most essential treatment goals are reducing pain and improving function.
The group advocated for NSAIDs as first-line pharmacologic therapy for AS and a biologic (TNF inhibitor or IL-17 inhibitor) as first-line biologic therapies when NSAIDs are insufficient. Other classes of biologic treatments, such as targeted synthetic DMARD (JAK inhibitor), could be used if initial treatments fail.
Clinician input suggested that patients would benefit more from upadacitinib, a selective JAK inhibitor for axial spondyloarthritis, given its unique mechanism of action and oral administration, which are considered ideal options for many patients, especially those who have failed treatment with continuous NSAIDs and continue to have high measures of disease activity. However, people with severe active infections, either acute or chronic, and people with severe hepatic disorders might not be suitable for upadacitinib use.
The drug programs provide input on each drug reviewed through CADTH’s Reimbursement Review processes by identifying issues that may affect their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 2.
Responses to Questions From the Drug Programs.
Two manufacturer-sponsored, double-blind, randomized controlled trials (14 weeks), Study 944 (N = 420) and Study 098 (N = 187), are included in this review. The 2 trials evaluated the efficacy and safety of upadacitinib 15 mg orally once daily compared with placebo in patients with active AS. Study 944 was conducted in patients with AS who inadequately responded or were intolerant to 1 or 2 bDMARDs. Study 098 was conducted in patients with AS who inadequately responded or were intolerant to at least 2 NSAIDs but bDMARD-naive. The primary outcome in both trials was the proportion of patients meeting the ASAS 40 response criteria at week 14. The key secondary outcomes (multiplicity controlled) included change from baseline in ASDAS; change from baseline in MRI SPARCC (spine) score; BASDAI 50 response; ASAS 20 response; ASDAS inactive disease (ASDAS < 1.3); change from baseline in patient’s assessment of total back pain (total back pain); change from baseline in patient’s assessment of nocturnal back pain (nocturnal back pain); ASDAS low disease activity (ASDAS < 2.1); change from baseline in BASFI score; ASAS partial remission; change from baseline in ASQoL score; change from baseline in ASAS Health Index score; change from baseline in linear Bath Ankylosing Spondylitis Metrology Index (BASMIlin) score; and change from baseline in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES).
Both Study 944 and Study 098 included 4 periods: screen period, double-blinded treatment period (for 14 weeks), extended treatment period (up to week 104), and posttreatment follow-up period (30 days after last visit). Both Study 944 and Study 098 were conducted in multiple countries, including Canada, the US, Europe, Australia, New Zealand, and Asian countries. Study 944 also included Mexico and countries from South America. Results of an extension phase at week 52 of both studies (Study 944 and Study 098) as well as week 104 for Study 098 are also presented in this report. Study 944 is still ongoing. The long-term efficacy and safety outcome at week 104 in Study 944 is not available at the time of this review. Study 098 was complete.
Clinical response (e.g., ASAS 40) at week 14: In Study 944, The proportion of patients who achieved ASAS 40 was reported as 44.5% and 18.2% in the upadacitinib 15 mg, orally, once daily (upadacitinib) group and the placebo group, respectively. The mean between-group difference (upadacitinib – placebo) was 26.4% (95% CI, 17.9% to 34.9%; P < 0.0001). In Study 098, the proportion of patients who achieved ASAS 40 was reported as 51.6% and 25.5% in the upadacitinib and placebo groups, respectively. The mean between-group difference (upadacitinib – placebo) was 26.1% (95% CI, 12.6% to 39.5%; P < 0.001). According to the clinical expert CADTH consulted for this review, ASAS 20 at week 12 has been considered an acceptable clinical response for bDMARDs trials in AS. Therefore, ASAS 40 at week 14 represents a more substantial clinical improvement, and more recent trials have used this as the primary end point.
Measures of AS symptoms (e.g., total back pain) at week 14: In Study 944, the mean changes from baseline for total back pain were −3.00 points (95% CI, −3.30 to −2.70) and −1.47 (95% CI, −1.77 to −1.16) in the upadacitinib and placebo groups, respectively. The mean between-group difference for change from baseline (upadacitinib – placebo) was −1.53 (95% CI, −1.96 to −1.11; P < 0.0001). In Study 098, the mean (95% CI) of changes from baseline for total back pain were –3.21 ████████████ and –1.68 ███████████ in the upadacitinib and placebo groups, respectively. The mean between-group difference for change from baseline (upadacitinib – placebo) was −1.53 (95% CI, −2.19 to −0.87; P < 0.001). The improvement of total back pain may be considered clinical meaningful (or useful) in both studies.
Function and disability (i.e., BASFI) at week 14: In Study 944, the mean changes from baseline for BASFI were −2.26 (95% CI, −2.53 to –2.00) and −1.09 (95% CI, −1.35 to –0.83) in the upadacitinib and placebo groups, respectively. The mean between-group difference for change from baseline (upadacitinib – placebo) was −1.17 (95% CI, −1.55 to −0.80; P < 0.0001). In Study 098, the mean changes from baseline for BASFI were −2.29 (95% CI, −2.73 to −1.85) and −1.30 (95% CI, −1.74 to −0.86) in the upadacitinib and placebo groups, respectively. The mean between-group difference for change from baseline (upadacitinib – placebo) was −1.00 (95% CI, −1.60 to 0.39; P < 0.001). The improvement of BASFI is considered clinical meaningful.
HRQoL (i.e., ASQoL) at week 14: In Study 944, the mean of changes from baseline for ASQoL were −5.10 (95% CI, −5.69 to −4.52) and −2.03 (95% CI, −2.62 to −1.44) in the upadacitinib and placebo groups, respectively. The mean between-group difference of change from baseline (upadacitinib – placebo) was −3.07 (95% CI, −3.90 to −2.24; P < 0.0001). In Study 098, the mean changes from baseline for ASQoL were −4.20 (95% CI, −5.12 to −3.29) and −2.67 (95% CI, −3.58 to −1.75) in the upadacitinib and placebo groups, respectively. The mean between-group difference for change from baseline (upadacitinib – placebo) was −1.54 (95% CI, −2.78 to 0.30; P < 0.016). The improvement in ASQoL is considered clinical meaningful in Study 944, but not in Study 098.
Work productivity (i.e., Work Productivity and Activity Impairment – Ankylosing Spondylitis [WPAI-SpA] Overall Work Impairment) at week 14: In Study 944, the mean (95% CI) of changes from baseline for WPAI Overall Work Impairment score were █████████████████████████████████████████████████████████ in the upadacitinib and placebo groups, respectively. The mean between-group difference for change from baseline (upadacitinib – placebo) was ███████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████. In Study 098, the mean changes from baseline for WPAI Overall Work Impairment score were −18.11 (95% CI, −24.73 to −11.50) and −12.60 (95% CI, −19.04 to −6.15) in the upadacitinib and placebo groups, respectively. The mean between-group difference for change from baseline (upadacitinib – placebo) was −5.52 (95% CI, −13.82 to 2.78; P = 0.19), which was not statistically significant.
Disease activity (e.g., ASDAS, BASDAI 50) at week 14: In Study 944, the mean changes from baseline for ASDAS (CRP) were −1.52 (95% CI, −1.64 to −1.39) and −0.49 (95% CI, −0.62 to −0.37) in the upadacitinib and placebo groups, respectively. The mean between-group difference for change from baseline (upadacitinib – placebo) was −1.02 (95% CI, −1.20 to −0.85; P < 0.0001). In Study 098, the mean changes from baseline for ASDAS (CRP) were −1.45 (95% CI, −1.62 to −1.28) and −0.54 (95% CI, −0.71 to −0.37) in the upadacitinib and placebo groups, respectively. The mean between-group difference for change from baseline (upadacitinib – placebo) was −0.91 (95% CI, −1.14 to −0.68; P < 0.001). A cut-off of 1.1 or higher is considered a clinically important improvement, which was seen in Study 944, but not in Study 098. In Study 944, the proportion of patients who achieved BASDAI50 (i.e., 50% decreased) was 43.1% and 16.7% in the upadacitinib and placebo groups, respectively. The mean between-group difference (upadacitinib – placebo) was 26.4% (95% CI, 18.0% to 34.8%; P < 0.0001). In Study 098, the proportion of patients who achieved BASDAI 50 at week 14 was 45.2% and 23.4% in the upadacitinib and placebo groups, respectively. The mean between-group difference (upadacitinib – placebo) was 21.8% (95% CI, 8.5% to 35.0%; P = 0.002). The response of BASDI 50 was considered clinical meaningful in both studies.
MRI SPARCC Index (spine) at week 14: In Study 944, the mean of changes from baseline for MRI SPARCC Index (spine) were −3.95 (95% CI, −5.06 to −2.83) and −0.04 (95% CI, −1.14 to 1.06) in the upadacitinib and placebo groups, respectively. The mean between-group difference for change from baseline (upadacitinib – placebo) was −3.90 (95% CI, −5.47 to −2.33; P < 0.0001). In Study 098, the mean of changes from baseline for MRI SPARCC Index (spine) were −6.93 (95% CI, −8.58 to −5.28) and −0.22 (95% CI, −2.01 to 1.57) in the upadacitinib and placebo groups, respectively. The mean between-group difference for change from baseline (upadacitinib – placebo) was −6.71 (95% CI, −9.01 to −4.41; P < 0.001). The improvement of MRI SPARCC Index (spine) was considered clinical meaningful in Study 098, but not in Study 944.
MASES at week 14: In Study 944, the mean changes from baseline for MASES were −2.6 (95% CI, −3.0 to −2.2) and −1.1 (95% CI, −1.5 to −0.8) in the upadacitinib and placebo groups, respectively. The mean between-group difference of change from baseline (upadacitinib – placebo) was −1.50 (95% CI, −2.00 to −0.90; P < 0.0001). But, whether the improvement of the MASES in Study 944 is clinical meaningful remains unclear. In Study 098, at week 14, the mean of changes from baseline for MASES were −2.25 (95% CI, −2.86 to −1.64) and −1.41 (95% CI, −2.02 to −0.80) in the upadacitinib and placebo group, respectively. The mean between-group difference for change from baseline (upadacitinib – placebo) was −0.84 (95% CI, −1.68 to 0.00; P < 0.049), which was considered not significant.
BASMI at week 14: In Study 944, the mean of changes from baseline for BASMI were −0.48 (95% CI, −0.58 to −0.38) and −0.16 (95% CI, −0.26 to −0.06) in the upadacitinib and placebo groups, respectively. The mean between-group difference of change from baseline (upadacitinib – placebo) was −0.32, 95% CI, −0.46 to −0.18. P < 0.0001. But, whether the improvement of BASMI in Study 944 is clinical meaningful remains unclear. In Study 098, the mean of changes from baseline for BASMI were −0.37 (95% CI, −0.52 to −0.21) and −0.14 (95% CI, −0.29 to 0.01) in the upadacitinib and placebo groups, respectively. The mean between-group difference for change from baseline (upadacitinib – placebo) was −0.22 (95% CI, −0.43 to −0.02; P < 0.03), which was considered not significant.
Efficacy reported in extension phase: The efficacy achieved at week 14 appeared to be maintained at 52 weeks ███████████████ and week 104 (for Study 098).
By week 14, the overall proportion of patients in the upadacitinib group with treatment emergent AEs (TEAEs) appeared low but was higher compared with the proportion in the placebo group in both Study 944 (40.8% versus 36.8%, respectively) and Study 098 (62.4% versus 55.3%, respectively). In Study 944, no TEAEs occurred in 5% or more of patients in either of the arms. In Study 098, the most common TEAEs (> 5% patients in either of the treatment groups) were increased blood creatine phosphokinase, diarrhea, nasopharyngitis, headache, and nausea. The overall frequency of patients with serious AEs (SAEs) seemed very low (< 3%) in both studies by week 14. No patients withdrew due to AEs in the upadacitinib group in Study 944. In Study 098, the proportion of patients that withdrew due to AEs was also very low (< 3%). No deaths were reported in either of the studies by week 14. The incidence of notable harms identified in this review was also low (including serious infection; anemia; neutropenia; lymphopenia; thrombocytopenia; malignancies; thrombosis, including increased platelets; elevation of creatine phosphokinase; other gastrointestinal SAEs; hypersensitivity; acne; and folliculitis). No major adverse cardiovascular events; gastrointestinal perforations; hepatotoxicity; dyslipidemia; opportunistic infection, excluding tuberculosis and herpes zoster; and active tuberculosis were reported. In either of the studies. Based on the clinical expert CADTH consulted for this review, the TEAE reported in both Study 944 and Study 098 were common TEAE as observed in other upadacitinib clinical trials for RA, psoriatic arthritis, and atopic dermatitis. Notable harms were nothing unexpected.
For the extension phase, the proportion of patients with TEAE were not reported in either of the 2 studies. Instead, the number of TEAEs and the number of TEAE person-years were provided. The clinical expert CADTH consulted for the review indicated that the safety profile of upadacitinib for AS over █████████████████████████ over week 104 was consistent with that observed by week 14, with no new safety signals reported. The overall observed AEs were aligned with the known safety profile of upadacitinib. No new safety signals were identified in weeks 14 to week 104.
Randomization appeared sufficient and blinding appeared to be maintained throughout the study. Missing data were minimal and unlikely to affect study results. The multiplicity adjustment was done for the primary and main secondary outcomes at week 14; however, in Study 944, no multiplicity adjustment was performed for other secondary outcomes or exploratory outcomes, such as ASAS 5/6 (The ASAS5/6 includes assessments of all 6 individual ASAS domains and represents improvement above or equal to 20% in at least 5 domains), HRQoL (5-Level EQ-5D [EQ-5D-5L], Short Form [36] Health Survey [SF-36]), Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F), WPAI-SpA, MRI SPARCC score (SI joints). In Study 098, no multiplicity adjustment was performed for symptom measurement scale (total back pain and nocturnal back pain), ASDAS Inactive Disease (ASDAS < 1.3), ASDAS low disease activity (ASDAS < 2.1); HRQoL (EQ-5D-5L,SF-36), FACIT-F, and MRI SPARCC score (SI joints). Given the large number of comparisons in the study, a statistically significant finding (P < 0.05) for the comparisons between upadacitinib and placebo for these outcomes without multiplicity adjustment may be a high risk of bias due to an inflated type I error rate. Therefore, the statistical significance (P value) reported for those outcomes without multiplicity adjustment remains uncertain. One limitation was that both Study 944 and Study 098 were not designed for assessing the comparative efficacy and safety between upadacitinib and the existing bDMARDs marketed in Canada (i.e., TNF inhibitors and IL-17 inhibitors) in the treatment of AS. Therefore, the direct comparative efficacy and safety evidence comparing upadacitinib with bDMARDs remains unknown. In addition, in both studies, the extra-articular manifestations were not assessed as an efficacy outcome in either of the studies. Therefore, the efficacy of upadacitinib on the extra-articular manifestations in the patients with AS remains to be investigated.
Limitations for long-term period: The findings at week 52 for both studies and at 104 weeks for Study 098 in the extension phase were limited by the lack of any control group and the nature of open label. Efficacy data beyond week 52 was not provided for the ongoing Study M19-944. The clinical experts CADTH consulted in this review indicated that, in clinical trials, it is common seen that the efficacy magnitude (especially, for those patient self-reported outcomes) often overestimated due to the nature of the open-label and no control group. Moreover, patients who enter into long-term extension are patients that are generally responding to the medication, or are aware they will now receive the medication, and are relatively free of AEs, which further increases biases observed around efficacy and safety. Therefore, the long-term outcome efficacy should be interpreted with the consideration of this limitation, although this would apply to all long-term extension studies. Finally, for the extension phase, the proportion of patients with TEAE were not reported in either of the 2 studies. Instead, the number of TEAEs and the number of TEAE person-years were provided.
The clinical expert CADTH consulted for this review indicated that exclusion of patients with total ankylosis of the spine and patients who had inadequate response to 2 and more bDMARDs in the trials were a “clinical trial strategy” to exclude patients that were not likely to demonstrate changes in numerous outcome measures. However, this is consistent with previous AS clinical trials (e.g., secukinumab, ixekizumab, anti-TNFs). In real life, it is possible that those patients with total ankylosis and who failed more than 2 bDMARDs may still demonstrate decreases in pain, stiffness, fatigue, and so on, and meaningful improvements in quality of life with the treatment. Overall, according to the clinical expert involved in the review, in both Study 944 and Study 098, the patients included in the trial are similar to those seen in Canadian clinical settings, except those patients with AS with total ankylosis of the spine and who had failed more than 2 bDMARDs would also be considered eligible for therapy would also be treated in clinic. There is little concern about the generalizability in Canada of the findings from both Study 944 and Study 098.
The sponsor submitted an ITC of upadacitinib in adults with AS and is included in this review. ██████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████ ██████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████
A focused literature search identified 2 published ITCs which are also included in the review.
██████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████ █████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████ ████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████
The published ITCs had similar findings. One used a frequentist approach and did not specify prior bDMARD exposure. The number of included studies was larger than the sponsor-submitted ITC. Fewer efficacy outcomes were assessed, but the ITC also included an assessment of SAEs. Upadacitinib was superior to placebo and no different than relevant comparators for efficacy outcomes. The other published ITC used a Bayesian approach to estimate comparative efficacy of JAK inhibitors and secukinumab in patients with no prior exposure to bDMARDs. Secukinumab was the only relevant comparator for the Canadian context included in this ITC. Upadacitinib was better than placebo and no different than secukinumab for efficacy outcomes.
███████████████████████████████████████████ The 2 published ITCs included comparative estimates for SAEs. In the ITC using a frequentist approach, upadacitinib was no different than placebo or other relevant comparators for SAEs. In the published ITC using a Bayesian approach, upadacitinib was no different than placebo or secukinumab for SAEs.
A key limitation in the sponsor-submitted ITC is the evidence base for patients who had an inadequate response to a previous bDMARD, which appears to be the primary target population for this drug based on the Health Canada indication. The ITC provides comparative efficacy for only ixekizumab and secukinumab in those with an inadequate response to a prior bDMARD. Although comparative efficacy is available for all relevant comparators in a bDMARD-naive population, it is uncertain if comparative efficacy results in bDMARD-naive patients can be generalized to patients who had an inadequate response to a bDMARD. The clinical expert consulted said that patients who responded inadequately to bDMARD would be expected to have a lower response compared with bDMARD-naive patients.
Another key limitation of the sponsor-submitted study is the presence of heterogeneity in baseline patient characteristics among studies. Additional aspects of study design may also contribute to heterogeneity. Many of the baseline characteristics with heterogeneity have been identified in the literature as treatment effect modifiers in AS. ███████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████████ Therefore, there is increased uncertainty in the ITC findings.
One of the 2 published ITCs had similar limitations related to heterogeneity of baseline patient characteristics among included studies while heterogeneity in the other study could not be evaluated because no baseline patient characteristics were provided. One study had additional concerns about heterogeneity related to time points used for efficacy assessment. Both ITCs also have limitations related to reporting of methods and results, as well as details about included studies.
No other relevant evidence was identified.
Two double-blind, randomized controlled trials of patients with active AS were included in this review. One (Study 944) was conducted in patients with inadequate response to or intolerance of 1 or 2 bDMARDs; the other (Study 098) was conducted in patients with an inadequate response to at least 2 NSAIDs, but who were bDMARD naive. The observed evidence indicated that, at week 14, once-daily, oral upadacitinib 15 mg showed a statistically significant and clinically meaningful (or useful) benefit as demonstrated by clinical response (e.g., ASAS 40), AS symptom reduction, function, and disability improvement, HRQoL, AS disease activity reduction, and MRI-detected axial inflammation compared with placebo. The treatment with upadacitinib also demonstrated a statistically significant improvement in terms of ASAS Health Index, MRI spine SPARCC change, enthesitis and spinal mobility compared with placebo at week 14 in study 944. Furthermore, the treatment with upadacitinib also appeared favourable compared with placebo in terms of WPAI and patient global assessment. The magnitude of clinical response (ASAS 40) to upadacitinib appeared similar in bDMARD-experienced patients compared with bDMARD-naive patients, although most clinical trials assessing efficacy in patients with an inadequate response to bDMARDs have demonstrated reduced treatment response. The efficacy achieved at week 14 appeared to be maintained at 52 weeks █████████████ and at week 104 in Study 098. The overall observed AEs were aligned with the known safety profile of upadacitinib. No new safety signals were identified at weeks 14 and up to week 104. The evidence from 3 ITCs suggests that no treatment for AS is favoured over others for most efficacy outcomes in bDMARD-naive patients and patients who had an inadequate response to a bDMARD, although the evidence base is limited in the latter population. No treatment is favoured over others for the outcome of SAEs. The presence of heterogeneity in the included studies increases uncertainty in the findings.
Cost and Cost-Effectiveness.
CADTH identified 2 key limitations to the submitted budget impact analysis. First, market size was estimated using a claims-based approach, which relies on aggregated data summarizing total prescriptions or claims. It was not clear what steps were taken to identify individual patients within these data. Second, market size estimates relied on 2 simplifying assumptions, which could not be verified. These related to the prevalence of adults with AS and the proportion of patients with AS with prior biologic experience. Although both limitations affected the size of the target population, the effect on estimated budget impact was unknown. In the absence of more reliable input values to address these limitations, the sponsor’s base case was maintained. The net budget impact of upadacitinib was estimated to be $445,516 in year 1, $2,282,075 in year 2, and $3,632,308 in year 3. The net budget impact over the 3-year time horizon was $6,359,899.
Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Dr. Alun Edwards, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Allan Grill, Mr. Morris Joseph, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Ms. Heather Neville, Dr. Danyaal Raza, Dr. Emily Reynen, and Dr. Peter Zed.
Meeting date: March 22, 2023
Regrets: One expert committee member did not attend
Conflicts of interest: None
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Indication: For the treatment of adults with active ankylosing spondylitis who have had an inadequate response to a biologic disease-modifying antirheumatic drug or when use of those therapies is inadvisable. Upadacitinib may be used as monotherapy or in combination with nonsteroidal anti-inflammatory drugs.
Sponsor: AbbVie Corporation
Final recommendation: Reimburse with conditions
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